Normative body mass-adjusted reference ranges of magnetic resonance imaging signs commonly used in diagnosing idiopathic intracranial hypertension in a healthy standard population

Patients with chronic daily headaches (CDH) are often a diagnostic challenge and frequently undergo neuroimaging. One common underlying cause of CDH is idiopathic intracranial hypertension (IIH). However, certain neuroimaging abnormalities that suggest IIH, such as optic nerve sheath diameters (ONSD), pituitary gland height, and venous sinus diameter, require interpretation due to the absence of established normative values. Notably, intracranial pressure is known to varies with age, sex and weight, further complicating the determination of objectively abnormal findings within a specific patient group. This study aims to assist clinical neuroradiologists in differentiating neuroimaging results in CDH by providing weight-adjusted normative values for imaging characteristics of IIH. In addition to age and BMI we here assessed 1924 population-based T1-weighted MRI datasets of healthy participants for relevant MRI aspects of IIH. Association to BMI was analyzed using linear/logistic regression controlled for age and stratified for sex. ONSD was 4.3 mm [2.8; 5.9]/4.6 mm [3.6; 5.7] and diameter of transverse sinus was 4.67 mm [1.6; 6.5]/4.45 mm [3.0; 7.9]. Height of pituitary gland was 5.1 mm [2.2;8.1]/4.6 mm [1.9;7.1] for female and male respectively. Values generally varied with BMI with regression slopes spanning 0.0001 to 0.05 and were therefor presented as normative values stratified by BMI. Protrusion of ocular papilla, empty sella and transverse sinus occlusion were rare in total. Our data show an association between BMI and commonly used MRI features for diagnosing IIH. We provide categorized normative BMI values for ONSD, pituitary gland height, and transverse sinus diameter. This distinction helps objectively identify potential IIH indicators compared to regular population norms, enhancing diagnostic accuracy for suspected IIH patients. Notably, optic nerve head protrusion, empty sella, and transverse sinus occlusion are rare in healthy individuals, solidifying their importance as imaging markers regardless of BMI.


Abbreviations
Chronic daily headaches (CDH) can have many different causes, which especially complicates the accurate diagnosis and thus also complicates the appropriate treatment.One common underlying cause of CDH is idiopathic intracranial hypertension (IIH).IIH first described by Quincke in 1893 as "meningitis serosa," is a disease of unknown exact pathophysiology.It most commonly affects young obese women of reproductive age.In this specific population, the incidence rate is 20 times higher than the estimated incidence of 20 per 100,000 in the general population [1][2][3] .Typical clinical signs include chronic daily headaches, which worsen with sudden increases in intracranial pressure such as the Valsalva maneuver.Other findings may include transient visual obscuration, retrobulbar pain, and pulsatile tinnitus, indicating increased intracranial pressure.
According to recently published evidence-based diagnostic criteria, definite IIH is still characterized by the clinical findings of papilledema and elevated cerebrospinal fluid pressure (CSF) 4 .However, neuroimaging criteria have been introduced, particularly for diagnosing IIH in instances lacking papilledema and for excluding secondary causes of elevated intracranial pressure when CSF pressure assessment is not readily accessible.
Imaging findings such as an empty sella turcica, alterations in the shape of the pituitary gland, enlarged optic nerve sheath diameter (ONSD), and stenosis or occlusion of the transverse sinus sigmoid have been reported in IIH and are included in the revised diagnostic criteria 5,6 .This is particularly relevant since clinical findings are not specific to IIH, and imaging findings can provide valuable diagnostic information.However, there are currently no normative values for typical imaging findings in IIH, as a physiological range is expected.Additionally, body mass index (BMI) may influence these normal values, as it can physically affect cerebrospinal fluid dynamics 7 and contribute to metabolic changes 8,9 .Therefore, establishing BMI-adjusted normative values specific to a population without headaches or neurological or ophthalmological abnormalities is crucial for accurately classifying MRI findings as abnormal and indicative of IIH.
The present study aims to address this gap by (1) examining the presence of typical imaging findings of IIH in a large population-based MRI study, (2) assessing the influence of body weight (as part of BMI), and (3) defining BMI-stratified normal values to improve the identification of pathological findings in patients with clinical suspicion of IIH.

Study population
The population-based Study of Health in Pomerania (SHIP) [10][11][12] consists of two independent cohorts representing the general population: SHIP-START-0 (n = 4308) and SHIP-TREND (n = 4420), with subsequent follow-up examinations (SHIP-START-1, n = 3300 and SHIP-START-2 n = 2333) 11 .The main objective of SHIP is to obtain a representative sample of the general population to assess the incidence and prevalence of common risk factors, as well as subclinical and clinical diseases, and investigate the complex relationships between these factors and conditions.The baseline cohorts were selected from the general adult population aged 20-79 years in West Pomerania, Northeast Germany 12 .All participants gave written informed consent.
For the present analysis, the cohorts of SHIP-START-2 and SHIP-TREND-0, which provided comprehensive anamnestic, clinical, and imaging data, were utilized as the basis.Along with detailed medical history obtained through structured interviews (including headache disorders), laboratory investigations, and a comprehensive clinical examination (including neurological and ophthalmological assessments, as well as BMI assessment), a total of 3368 subjects underwent whole-body MRI (see also 12,13 ).
The initial selection for further MRI evaluation included the first 2000 complete MRI datasets from participants who had no history of recurring headache within six months prior to study inclusion, no known headache disorder, no observed neurological abnormalities during clinical examination, no ophthalmological disease, no history of brain injuries or neurosurgical procedures, and no radiological abnormalities.An additional 76 participants were subsequently excluded due to low imaging quality.As a result, 1924 participants were available for the present analysis.In addition to MRI, sex, age, and BMI were recorded for all participants.

Institutional review board statement
The studies were conducted in accordance with the Declaration of Helsinki.The study protocols were approved by the responsible local ethics committee at the University of Greifswald 12,13 .

Image analysis
For image analysis, all MR datasets were transferred to an Osirix DICOM workstation (Osirix Vers.6.0, Pixmeo, Geneva, Switzerland), and additional multiplanar reconstruction in the parasagittal and coronal planes was performed.The sagittal plane was angulated along the axis of the orbit.Image analysis was performed using a standardized window/level setting for all datasets and a standardized zoom factor of 800%.The following signs of IIH on MR images were evaluated in the T1w datasets.Despite the quality check applied to all MRI scans before their inclusion in the analysis, there were instances during the analysis where suboptimal imaging quality for specific signs, resulted in the designation of the sign as 'non-evaluable.' Consequently, it was not included in the final analysis.

Optic nerve diameter and optic nerve sheath diameter
For evaluation the diameter of the optic nerve (OND) and nerve sheath (ONSD) the axial imaging plane was adjusted to perpedicular to the course of the optic nerve.The measurement was conducted separately for each side, perpendicular to the axis of the optic nerve, 8 mm posterior to the posterior circumference of the globe (Fig. 1a), as described elsewhere 14 .

Optic nerve tortuosity
The trajectory of each optic nerve was evaluated in the sagittal and horizontal planes using a drawn straight line.The trajectory was categorized as either straight or meandered (curved or S-shaped) 15 .

Shape of optic nerve head and posterior contour of the globe
In the axial plane at the level of the optic head, the shape of the globe was assessed as either flattened or round, and the optic nerve head was examined for flattening or bulging using auxiliary lines (Fig. 1a), based on 15 .

Height of the pituitary gland
The height of the anterior pituitary gland was measured in the median sagittal plane of the sella 16 .The individual median sagittal plane was identified for each subject (Fig. 1b).An empty sella was recorded if no identifiable anterior pituitary gland was present.

Diameter of the transverse sinus
The minimum diameter of the transverse sinus was measured individually for each side in the axial and sagittal planes, following the approach described by Bianchi et al. 16 (Fig. 1c,d).If the transverse sinus was not discernible, it was categorized as hypoplastic or occluded 17,18 .
One reader (RK) examined all MRI datasets.As part of quality control, a randomly chosen subset of 70 datasets underwent re-evaluation by a board-certified neuroradiologist with 15 years of experience in brain MRI imaging.Intra-class correlation coefficients (ICC) were computed for all continuous variables, such as optic nerve sheath dimensions, pituitary gland height, and transverse sinus diameter.The ICC is a statistical method used to gauge the consistency of measurements or quantitative assessments.The ICC analysis demonstrated substantial agreement between the two raters for all continuous MRI variables (ICC > 0.9).

Statistical analysis
Descriptive statistic of all continuous variables is provided as mean and standard of the mean.Reference values for each MR parameter are presented as median with the 2.5th and 97.5th percentiles stratified by sex, excluding cases with "empty sella" or occluded sinus transversus.Finings occurring on both sides without significant side differences were averaged for further analyses.
Association between BMI and the measured continuous MR parameters was analyzed using linear regression analysis controlled for age and stratified by sex.For categorial outcome variables (Occurrence of ……) logistic regression analyses were used.
Statistical analysis was performed with STATA version 13.1, and a p-value < 0.05 was a priori defined as indicating a statistically significant difference.

Sample description
The final analysis comprised 1924 MRI datasets, including 950 males and 974 females.Participants had a mean age of 47.68 years (ranging from 20 to 80 years), and the mean BMI was 26.8 kg/m 2 (ranging from 18.5 to 45.4 kg/ m 2 ).Further details can be found in Table 1.
Table 1.Descriptive statistic of all continuous variables provided as median with 2.5th and 97.5th percentiles (square bracket).*Indicating significant associations to BMI.

Presence of typical imaging findings of IIH and influence of bodyweight
Optic nerve diameter Optic nerve diameter showed a significant correlation with BMI in women (β = 0.01, p = 0.020) but not in men (β = 0.0001, p = 0.981) (Fig. 2a,b).

Optic nerve sheath
For ONS, linear regression analysis reveals a significant correlation between diameter and BMI in women (β = 0.01, p = 0.004) but not in men (β = 0.01, p = 0.063) (Fig. 2c,d).www.nature.com/scientificreports/Optic nerve tortuosity Logistic regression analyses showed no significant association between BMI and the likelihood of a meandered optic nerve.

Shape of optic nerve head and posterior contour of the globe
Logistic regression analyses did not reveal any statistically significant correlation between BMI and the likelihood of the occurrence of bulging of the optic nerve head or flattening of the posterior contour of the globe.

Height of the pituitary gland
There was an inverse association of BMI and height of the pituitary gland for females (β = − 0.05, p = 0.001) as opposed to males (β = 0.04, p = 0.001) (Fig. 2e,f).

Diameter of transverse sinus
Since body weight did not have an impact on the symmetry of the transverse sinus (absolute difference left/right: women (t (971) = − 1.28, p = 0.199; men (t (947) = 0.03, p = 0.97)), the diameters of the left and right sides were averaged for further analysis.Linear regression analysis demonstrated a significant association between BMI and sinus diameter in women (β = − 0.03, p < 0.001) and men (β = − 0.03, p = 0.004) (Fig. 2 g,h).

Normal values stratified for body weight
Due to the significant association between body weight and most of the evaluated MRI signs, with some differences related to sex, we established normal values for the optic nerve diameter (OND), optic nerve sheath diameter (ONSD), height of the pituitary gland, and transverse sinus diameter stratified by BMI and sex.

Optic nerve tortuosity
Out of the 1924 participants, 53 individuals (2.8%; 22 females) exhibited a meandered course in one of the two optic nerves.Only one participant showed an altered course bilaterally.In 1870 participants (97.2%), the course of both optic nerves was classified as straight (Fig. 4).

Diameter of transverse sinus
The mean diameter of the transverse sinus on axial T1-weighted images was 4.67 mm [1.6; 6.5] for females and 4.45 mm [3.0; 7.9] for males (Table 1, Fig. 3d).In 57 participants (3%, 28 females), at least one of the transverse sinuses (right: n = 24; left: n = 29; both: n = 4) was not detectable on axial and sagittal images and was therefore classified as occluded or absent.No significant difference was observed based on sex (Fig. 7).

Discussion
Imaging plays a crucial role in the diagnostic work-up of patients with suspected IIH by aiding in the exclusion of secondary causes.In our population-based MRI study, we observed a significant association between BMI and several important imaging parameters, including OND, ONSD, height of the pituitary gland, and transverse sinus diameter.These findings are particularly relevant as they are considered key imaging features in the diagnosis of IIH.

Optic nerve diameter, optic nerve sheath diameter and course of the optic nerve
The mean values of optic nerve diameter in our study align well with existing literature on healthy participants 17 .
Although there were no significant differences in the mean values based on sex, we observed a significant association between optic nerve diameter and BMI, specifically in women.However, the medical significance of OND in the pathophysiology of neurological diseases remains unclear, as MRI studies focusing on this parameter are rare.In contrast, the enlargement of ONSD is directly associated with intracranial pressure, both in healthy individuals 18 and in patients with IIH 19 .Although sensitivity (0.45-0.66) and specificity (0.82-0.95) of enlarged ONSD in relation to elevated intracranial pressure vary widely in the literature 20 , this MRI parameter is frequently utilized in the diagnostic process.On MRI, enlargement of the optic nerve sheath (ONS) appears as a widened ring of cerebrospinal fluid (CSF) around the intraorbital course of the optic nerve with isointense signal to CSF on both sides of the nerve in axial and coronal images.The ONSD in our study is comparable to previous reports 14 .Unlike previous ultrasound studies, we did not observe any differences between men and women in our MRI measurements 20 , but we did find a positive correlation between ONSD and BMI, which has not been previously described 21 .
Interestingly, a meandering course of the optic nerve, optic nerve head protrusion, and flattening of the posterior aspect of the globe were observed in less than 2% of all participants.We therefore postulate that ONSD is a highly sensitive surrogate parameter for intracranial pressure, which may be increased due to higher BMI without being clinically relevant 22 .
Conversely, findings like meandering course of the optic nerve, optic nerve head protrusion, and flattening of the globe might occur more frequently in patients with clinically relevant increased intracranial pressure.This conclusion is supported by a recent study by Witsberger et al. 23 in which they suggest that raised intracranial pressure is a continuum, with even asymptomatic individuals demonstrating abnormal findings on brain MRI.Our assumptions are further supported by a recent meta-analysis of IIH patients by Kwee and colleagues 6 who reported high specificity for optic nerve course, optic nerve head protrusion, and flattening of the posterior globe in patients with IIH, while ONS diameter exhibited high variability in the analyzed literature.

Height of the pituitary gland
Sex-related differences in hormonal activity are thought to be responsible for the observed differences in pituitary gland height, with larger pituitary glands observed in females 24 .In female patients, we also identified a correlation between pituitary gland size and BMI.These findings align with a recent study by Witsberger et al. 23 , who observed a direct correlation between the ratio of pituitary gland height relative to the sella and opening pressure on lumbar puncture for CSF analysis.However, we observed inverse association of BMI and height of the of pituitary gland for females as opposed to males.Whether this observation is related to differences in hormonal activity needs to be further evaluated in subgroup analyses.The presence of an empty sella was observed in 3.3% of our study population, which is lower than the prevalence reported in previous studies 25 .We did not find any correlation between BMI and the presence of an empty sella, regardless of sex.In the interpretation of the findings, it is essential to emphasize that we are presenting the height of the pituitary rather than its ratio to the sella 4 .Therefore, a precise categorization of pituitary morphology based on the degree of suprasellar herniation of cerebrospinal fluid into the sella, as conducted by other authors, is not feasible.

Diameter of the transverse sinus
In a recent meta-analysis by Kwee et al., it was reported that alterations in the diameter of the transverse sinus were the only MRI sign with high pooled specificity and reasonably high sensitivity in diagnosing IIH 6 .Previous studies have also reported a negative correlation between invasively measured venous pressure gradients in the transverse sinus and the diameter of the sinus in patients with IIH 26 .However, our data demonstrates a significant negative correlation between sinus diameter and BMI.This finding may support the hypothesis of a relationship between overweight, increased intraabdominal pressure, subsequent extracranial venous pressure, and increased intracranial pressure, resulting in a decreased diameter of the sinus.Whereas the rate of transverse sinus occlusion in patients with secondary IIH can be as high as 94% 27 we observed transverse sinus occlusion in our healthy cohort on one side only in 2.7% of participants and bilaterally in 0.2%.These findings are consistent with previous studies 28 and emphasize the significance of the radiological finding of sinus occlusion in the diagnostic process of IIH.
The present study has several strengths, including its large sample size derived from a representative general population.The retrospective design allowed for the assessment of the effects of sex and BMI on the evaluated MRI parameters.However, there are also limitations to consider.Firstly, it should be noted that the analysis was exclusively conducted using T1 images, which often is a common practice in clinical settings.However, the significance of the findings could potentially be enhanced by incorporating additional 3D heavily T2-weighted images and dedicated MR venography sequences.The absence of the latter limited the evaluation of the transverse sinus especially since diameter measurement was performed only at a predefined position rather than along the entire course of the sinus.
Secondly, the absence of data regarding lumbar puncture opening pressure, a pivotal method in the diagnostic evaluation of suspected idiopathic intracranial hypertension (IIH), poses a limitation.This is particularly noteworthy given the apparent association between adipose tissue and intracranial hypertension.However, the precise correlation with the current cerebrospinal fluid (CSF) pressure remains unclear.The actual pressure seems to be more closely associated with CSF production and absorption 29 .Conversely, BMI appears to play a role in the predisposition and likelihood of developing the condition.Based on our data, one can only speculate about the potential influence of BMI on the opening pressure itself.Notably, the European Headache Federation (EHF) Guidelines recognize a grey zone between 25-30 cm H2O in obese patients.It may be appropriate to state that the influence of BMI on the opening pressure is "uncertain," but referring to the EHF guidelines aligns well with our findings, suggesting that the opening pressure might be "marginally" affected 30 .
Additionally, due to the representative nature of the data for the general population, there were only a few cases of suspected or diagnosed IIH included, which limited the availability of a direct patient control group.Future studies should aim to replicate the reference data obtained from healthy individuals in a large cohort of patients with IIH to further validate the findings.

Conclusion
In a population-based MRI study involving participants without any clinical evidence of headache disease, we identified significant correlations between BMI and parameters such as ONSD, pituitary gland height, and transverse sinus diameter.These correlations hold implications for the diagnostic evaluation of patients with suspected IIH.Our study contributes BMI-stratified normal values that complement the existing literature and can enhance diagnostic precision in the future.Furthermore, we observed that specific imaging criteria, such as the course of the optic nerve, protrusion of the optic nerve head, and occlusion of the transverse sinus, were infrequent among asymptomatic individuals.Despite considering BMI, these criteria could have significance in the diagnostic process for patients suspected of IIH.
Aligning with our findings, recent literature has shown high sensitivity and notably exceptional specificity of various MRI aspects, but only when employed as a composite diagnostic criterion for IIH 4,31 .Nevertheless, this underscores their potential significance in the clinical assessment of suspected IIH.

Figure 1 .
Figure 1.Measurement of optic nerve diameter (a, arrow), optic nerve sheath diameter (a, dotted arrow), height of the pituitary gland (b, arrow) and sinus transversus diameter (c: arrow).Middle part of sinus transversus was identified in the axial plane, measurement was than performed in axial plane (d: dotted line indicates sectional plane of the sagittal image c).

Figure 2 .
Figure 2. Linear regression of associations of BMI (kg/m 2 ) and diameter of optic nerve (a,b), optic nerve sheath (c,d), high of pituitary gland (e,f) and sinus transversus diameter (g,h) in both female (left) and male (right).

Figure 3 .
Figure 3. BMI-related reference ranges of optic nerve diameter (a), optic nerve sheath diameter (b), height of pituitary gland (c) and sinus transversus diameter (d) depending on BMI for both females (red lines) and males (blue lines) given as 97.5th percentile and 2.5th percentile.Dotted line indicates the median.

Figure 4 .
Figure 4. Variations in the course of the optic nerve on axial T1-weighted images; (a) 37-year-old female participant with straight course of the optic nerve (white arrow).(b) 39-year-old female participant with meandering course within the orbit (dotted white arrow).

Figure 5 .
Figure 5. Variations in the shape of the optic disc on axial T1-weighted images.(a) 42-year-old male participant with flat optic disc (white arrow) and straight course of the optic nerve.(b) 43-year-old female participant with bulging of the optic disc (dotted white arrow), enlarged subarachnoid space and meandering course of the optic nerve.